Diffuse large B cell lymphoma

What every physician needs to know:

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that is potentially curable. DLBCL is the most common non-Hodgkin lymphoma (NHL) representing about 25-35% of all new cases of NHL in the United States of America (USA) and Europe. The disease can manifest de novo or through transformation from less aggressive lymphomas. There are over 76 different types of lymphoma in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. It is essential to establish the correct histological diagnosis prior to treatment.

The prognosis has been defined by five independent prognostic factors: age, performance score, lactate dehydrogenase (serum), extranodal sites, and stage (APpLES), which assigns individual patients to low, low/intermediate, high/intermediate, or high. This dichotomous cutpoint scale, which lacks calibration, was developed before the rituximab era. It is this risk factor stratification that remains predictive in the immunochemotherapy era.

The addition of rituximab to chemotherapy and immunochemotherapy, changed the natural history of DLBCL.

New biologic observations are contributing to new approaches to DLBCL.

Are you sure your patient has diffuse large B cell lymphoma? What should you expect to find?

The most common presentation is painless lymphadenopathy in a patient with no accompanying symptoms. Patients may present with extranodal disease.

The symptoms of lymphoma include the classical "B" symptoms of fevers, night sweats, and weight loss. Other symptoms relate to the location of the nodal or extranodal disease.

Beware of other conditions that can mimic diffuse large B cell lymphoma:

The differential diagnosis of lymphadenopathy broadly includes cancers, hypersensitivity syndromes, infections, connective tissue diseases, atypical lymphoproliferative disorders, granulomatous disorders, and other unusual causes. An acronym for this is CHICAGO. There are more than 158 causes of lymphadenopathy as broadly classified. The malignant causes include the hematologic malignancies including other non-Hodgkin lymphomas, Hodgkin lymphoma, acute and chronic leukemias, and other disorders and solid tumors including breast cancer, lung cancer, renal cell carcioma, prostate cancer, and others. There are over 76 different types of non-Hodgkin lymphoma which must be differentiated from DLBCL.

Which individuals are most at risk for developing diffuse large B cell lymphoma:

The cause is unknown in the majority of patients with DLBCL. DLBCL is the most common NHL. From 1973 to 1997, the overall incidence of NHL increased by 81.3%, and research has still not established the primary reason for this.

Abnormalities in the immune system are the major risk factors for DLBCL. These include:

Immunodeficiency (HIV): DLBCL is an AIDS defining disease in 2 to 3% of individuals

DLBCL is the most common histology in lymphoproliferative diseases associated with primary immune disorders such as:

Common variable immune deficiency syndrome

Severe combined immunodeficiency syndrome

X-linked lymphoproliferative disorder

Autoimmune lymphoproliferative syndrome

The Epstein Barr Virus is associated with HIV, primary immune disorders, EBV positive DLBCL of the elderly, and 5 to 10% of DLBCL not otherwise specified (NOS).

Patients with indolent NHL may transform to DLBCL. The risk was 3% per year in patients with follicular lymphoma in the pre-rituximab era and 2% per year in patients previously treated with rituximab.

There is an increased risk of NHL in family members. First degree family history of NHL has been reported by 6% of patients, leukemia in 4%, and both in 1%.

On review of 101 studies of occupational, military, and accidental exposure to pesticides, the collective epidemiologic data do not provide compelling evidence for a causal relationship with NHL.

Factors not associated with DLBCL include smoking, hair dye usage after 1980, meat consumption, and occupational or wartime exposure to ionizing radiation.

There are factors which appear to decrease the risk of developing DLBCL. Most studies report an inverse association with fruit and vegetable intake, current alcohol intake, and sun exposure.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The essential laboratory test is a tissue biopsy of a lymph node or extranodal tissue. Tissue biopsy with surgical removal is the preferred approach. Multiple core needle biopsies are utilized in sites that are difficult to approach. In general, fine needle aspirates are insufficient and are not recommended as an initial diagnostic approach. The 2008 WHO classification includes DLBCL-NOS as a category that includes the germinal center B-cell (GCB) and activated B-cell (ABC) subtypes and other cases of DLBCL that include T-cell/histiocyte-rich large B-cell lymphoma, primary central nervous system DLBCL, primary cutaneous DLBCL leg type, and EBV+ DLBCL of the elderly.

The classification of lymphoma is based on morphology and immunophenotype. The pathologist utilizes selected markers, which are dependent upon the light microscopy findings. No one antigenic marker is specific for any lymphoma, and so a combination of morphologic features, and a panel of antigenic markers are required for the correct diagnosis of NHL, and specifically DLBCL. DLBCL is a B-cell lymphoma and so it characteristically expresses CD20, CD19, and CD79a and is CD-3 negative. In addition, there is characteristically kappa or lambda light chain restriction. These studies can be performed by slide based immunohistochemistry or flow cytometry.

DLBCL has been subclassified through gene expression profiling (GEP) into germinal-center B (GCB) cell-like DLBCL and activated B-cell (ABC)-like DLBCL with 5-year overall survival (OS) in the GCB group of 76% compared to 34% in the non-GCB group. Several algorithms using formalin-fixed, paraffin-embedded tissue, and immunohistochemical techniques have been reported, which can translate the GEP studies. The Hans algorithm is commonly employed with CD10, multiple myeloma oncogene 1 (MUM1), and polyclonal B-cell lymphoma 6 (BCL6) to assign cases, and has an 80% concordance with GEP. Patients with GCB subtype are CD10+ or BCL6+ and MUM1 negative, and patients with ABC are CD10- and BCL6-and MUM1 positive. Patients with an ABC type DLBCL have an inferior outcome, but there are no current guidelines specific for these DLBCL subtypes. In a phase II study, lenalidomide combined with R-CHOP (R2CHOP) overcomes the negative prognostic impact of the non-germinal center phenotype in DLBCL and a randomized phase II study is ongoing. Studies with ibrutinib combined with R-CHOP are currently ongoing.

Newer approaches are incorporating fluorescence in situ hybridization to detect breakpoints in BCL2, BCL6, and MYCor other antibodies. MYC translocations have been reported in 5 to 14% of patients, and these patients have an inferior outcome, especially if associated with BCL2 or BCL6. If associated with one of these it is referred to as a double hit and if both, a triple hit. These patients have a worse prognosis.

Some DLBCL cases are difficult to differentiate from Burkitt lymphoma. These are now classified as B-cell lymphoma, intermediate between Burkitt lymphoma and DLBCL as current morphology, immunophenotype, and genetic abnormalities are not reliably reproducible. In addition, some cases of B-cell lymphoma are intermediate between primary mediastinal B-cell lymphoma and classical nodular sclerosing Hodgkin lymphoma.

At this time, there are many ongoing efforts involving microarray, single nucleotide polymorphisms, whole-genome sequencing, which are discovering new somatic mutations and potential targets. This technology is currently at a research level, and not applicable in routine diagnosis approaches.

A complete blood count and differential are required. The differential assures that the absolute neutrophil count is greater than 1,500 for chemotherapy. In addition, the absolute lymphocyte/monocyte ratio of less than 1.1 predicts an inferior progression-free and overall survival.

A chemistry group serves to evaluate the function of other key organs including renal and liver function. Patients with DLBCL may present with hypercalcemia. Hyperuricemia may be present at diagnosis, or be a very early complication of the first treatment cycle. The lactate dehydrogenase is a prognostic marker in DLBCL and is incorporated into the International Prognostic Index (IPI).

Bone marrow aspiration and biopsy is recommended to stage patients, and assure that there are no other underlying bone marrow abnormalities. The overall incidence is lower, less than 5%, in patients with stage I and II disease, and a routine bone marrow study may not be indicated.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of diffuse large B cell lymphoma?

Computed tomography (CT) scan of chest/abdomen/pelvis, with oral and intravenous contrast (unless renal insufficiency), are the standard staging procedures. 18-Fluoro-deoxyglucose positron emission tomography-computed tomography (FDG-PET-CT) scan is now utilized in the initial staging, and in restaging at some cycle interval (two to four) to assess response and prognosis.

Patients with negative interim scans have a very good prognosis, with about 85% negative predictive values. In contrast, patients with positive interim scans have a 13 to 75%, 2 year disease free survival. An intermediate positron emission tomography (PET) scan is more likely a negative scan. The current National Comprehensive Cancer Network (NCCN) guidelines include PET-CT as optional in the initial work-up. FDG-PET-CT is not recommended for the routine follow-up of patients.

CT or MRI of the appropriate nervous system area are required if central nervous system (CNS) disease is of concern.

An echocardiogram or multiple-gated acquisition (MUGA) scan is essential when treating patients with anthracycline chemotherapy regimens which are the mainstay of treatment.

If you decide the patient has diffuse large B cell lymphoma, what therapies should you initiate immediately?

The emergencies in DLBCL are related to bulky presentations and include subacute and acute superior vena cava (SVC) syndrome, acute renal failure secondary to ureteral obstruction, hypercalcemia, and severe hyperuricemia.

Urgent chemotherapy, with or without radiation therapy is required in acute SVC syndrome, secondary to large mediastinal masses in either advanced DLBCL or in primary mediastinal (thymic) large B-cell lymphoma. It is imperative to obtain an adequate tissue biopsy prior to treatment with any agents, including corticosteroids.

It is essential to protect the kidneys. Allopurinol is routinely recommended immediately prior to, and with the initial treatment. Lymphomatous masses may obstruct the ureters. Urologic consultation with ureteral stent placement is required prior to treatment. Hypercalcemia requires standard approaches, in addition to treatment with primary chemotherapy. Hyperuricemia may be managed with allopurinol or, in selected cases, rasburicase, if uric acid is rising despite allopurinol and a rising creatinine.

Hepatitis reactivation has been reported with patients treated with either chemotherapy or rituximab. Treatment with rituximab is a risk factor. In patients who are hepatitis positive, hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive, empiric antiviral therapy is recommended if viral reactivation is documented.

More definitive therapies?

The standard of care in DLBCL is six cycles of rituximab/cyclophosphamide/doxorubicin hydrochloride/vincristine/prednisolone (R-CHOP), administered every 21 days. The Groupe d'Etude des Lymphomes (GELA) randomized untreated patients 60 to 80 years of age to R-CHOP (rituximab, cyclophosphamaide, doxorubicin hydrochloride, vincristine, and prednisolone) versus CHOP. The benefit was observed in both low-risk and high risk IPI groups. The median progression free survival, 1.5 years for CHOP versus not reached for R-CHOP, and the median overall survival (OS) was 3.1 years for CHOP and not reached for R-CHOP. The 7 year OS was 53% for CHOP and 65% in the R-CHOP arm. The ten-year overall survival was 43.5% in the R-CHOP arm and 27.6% in the CHOP arm. The US Intergroup study confirmed these results, and reported that there was no benefit to maintenance rituximab.

The MabThera International Trial (MInT) randomized young patients with 0 to 1 risk factors, stage II to IV disease, or stage I with bulky disease to CHOP-like therapy, versus CHOP-like therapy plus rituximab. The 3 year OS was superior in the rituximab arm at 93% versus 84% (P = 0.0001).

Males over the age of 60 have inferior outcomes with rituximab as women in this age group metabolize the drug slower. Lymphoma occurring during pregnancy requires special staging and treatment considerations.

In patients with limited stage disease, the standard of care is more limited therapy. Bulky stage II disease patients have similar responses to patients with advanced disease. A stage-modified IPI identifies groups of patients. Limited-disease patients have no adverse factors (stage I, younger age, normal serum lactate dehydrogenase (LDH), and good performance status). These patients have a 95 to 97% OS at 5 years. Patients with at least one risk factor are identified by the stage modified IPI (nonbulky stage II disease, age greater than 60 years, WHO performance status of two, or elevated serum lactate dehydrogenase). In these later patients, three cycles of R-CHOP chemotherapy, followed by 40 to 46Gy of involved field radiation therapy, resulted in a 4 year progression free survival (PFS) of 88% and 4 year OS of 92%. An alternative approach is six cycles of chemotherapy. More recent studies have been evaluating the role of the incorporation of radioimmunotherapy.

The role of consolidation radiation therapy (RT) for patients has been controversial and has not been adequately studied in the immunochemotherapy era. The German High Grade Lymphoma Study Group has reported that additional radiotherapy has no role with an OS in R-CHOP treated patients in complete remission (CR), or complete remission/unconfirmed (CRu) of 76% versus 80% in R-CHOP/RT treated patients.

In trials of variable cycle length randomizing patients to R-CHOP21 versus R-CHOP14, R-CHOP14 was not superior and was associated with more toxicities and costs, including the routine use of growth factors.

More intensive approaches have been evaluated in randomized studies. R-MegaCHOEP (high dose [HDT] cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone administered every 21 days and hematopoietic stem cells were harvested after cycles 1 and 2 and reinfused after HDT cycles 2,3, and 4) versus R-CHOEP-14 demonstrated no differences in OS or PFS. In the USA, the Southwestern Oncology Group compared CHOP (215) or R-CHOP (182) for five cycles and then randomized patients with intermediate, high intermediate, and high risk disease in PR or CR to three more cycles of chemotherapy, versus one more cycle of chemotherapy and autologous stem cell transplantation. There was no improvement in OS (74% versus 71%). The GELA reported that rituximab/Adriamycin/cyclophophamide/vindesine/bleomycin/prednisone (R-ACVBP) was superior to R-CHOP21, but this regimen was more toxic. In addition, vindesine is not available in the USA.

The infusion regimen DA-EPOCH-R (dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) is effective in all biomarker groups, and is currently under evaluation in a randomized phase III study, led by the Alliance with R-CHOP21 and the study is ongoing.

Patients with DLBCL diagnosed after transformation from low grade lymphomas have traditionally been reported to have a poor prognosis compared to de novo DLBCL. However, in the rituximab era, patients who transformed greater than 18 months after follicular lymphoma diagnosis had a 5-year OS of 66% versus 22% in those who transformed earlier. Transformation is associated with accelerated disease progression and the emergence of drug resistance. Patients are treated with R-CHOP21. Those patients that achieve a complete remission are optimally managed with a peripheral blood stem cell transplant in first complete remission.

What other therapies are helpful for reducing complications?

Allopurinol at a dose of 300mg per day for 10 days is recommended at the time of the initial dose of chemotherapy for DLBCL.

The American Society of Clinical Oncology (ASCO) guidelines should be followed for the use of hematopoietic colony-stimulating factors (CSF). They are recommended when the risk of febrile neutropenia (FN) is approximately 20%, and no other equally effective regimen that does not require colony stimulating factors is available. Primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimens.

Dose-dense regimens have not been demonstrated to be superior in randomized trials to date in DLBCL. Therefore, dose-dense regimens should only be used in clinical trials. The ASCO guidelines recommended the prophylactic use of CSF in patients with diffuse aggressive lymphoma aged 65 and older, that are treated with curative chemotherapy (CHOP or more aggressive regimens) to reduce the incidence of FN and infections.

What should you tell the patient and the family about prognosis?

The overall prognosis changed for the first time in 25 years with the addition of rituximab to CHOP chemotherapy. In the USA, the mean overall survival at 5 years is currently 66.8%. This is supported by randomized trials and a Canadian population study. If the patient is alive and disease-free with no intervening treatments after the initial treatments, then the overall survival is equivalent to that of the age- and sex-matched general population.

In an individual patient, it is essential to relate potential outcome to age, stage, serum lactate dehydrogenase, performance status, and number of extranodal sites. The original IPI publication from the pre-rituximab era was based on the number of negative prognostic factors present at the time of diagnosis (age greater than 60 years, Eastern Cooperative Oncology Group [ECOG] performance status greater than or equal to two, elevated lactate dehydrogenase [LDH] level, more than one extranodal site of disease, and stage III/IV disease); the 5 year survival rates in the four risk groups were 73%, 51%, 43%, and 26%. In an age adjusted model for patients less than 60 years of age, the five-year survival rates were 83%, 69%, 46%, and 32%. The prognostic ability of the IPI remains in the rituximab era.

In addition, the assessment of response to initial therapy by PET scan after two to four cycles of treatment, predicts an over 85% chance of not relapsing if negative. Routine PET scans to follow asymptomatic patients are not indicated.

Six retrospective studies have demonstrated that post-therapy surveillance scans in asymptomatic patients in complete remission with an unremarkable physical examination and laboratory studies add little to the detection of relapse and fail to demonstrate a survival benefit. Scan only relapse rates in these series ranged from 1-9%. There are no prospective clinical trials that have evaluated this question. Routine scans are definitely not indicated two years after the diagnosis in the majority of asymptomatic patients.

"What if" scenarios.

What if the patient develops fever during a chemotherapy cycle?

This is most likely febrile neutropenia secondary to an infection.

What if the patient progresses during treatment, is refractory to treatment, or relapses at some time period after achieving a complete remission?

Each of these scenarios has a different prognosis. In those patients who are transplant eligible which includes patients without comorbidities under the age of 75 years, treatment with salvage therapy, followed by high-dose therapy and autologous stem cell transplantation is the standard of care. In a recent study randomizing patients to rituximab/dexamethasone/cytarabine/cisplatin (R-DHAP) or rituximab/ifosfamide/carboplatin/etoposide (R-ICE), the overall response rate (ORR) was 63% with a complete remission (CR) rate of 38%.

Approximately half of patients are able to move on to high-dose therapy and autologous transplant. Patients who relapse less than 12 months after initial rituximab chemotherapy, have a worse outcome with transplant. Approximately 40% of patients who are in complete remission after RDHAP or RICE are in long-term remission.

What if the patient relapses after transplant?

These patients are eligible for clinical trials. Oral agents are currently under study. Everolimus at a dose of 10mg per day resulted in an overall response rate of 36%. Lenalidmide is active in relapsed/refractory DLBCL and is now under evaluation in combination with R-CHOP. New anti-CD20 monoclonal antibodies are in clinical trials. Bruton's tyrosine kinase inhibitor agents are under evaluation in combination with R-CHOP. Other drugs are under evaluation that target different aspects of DLBCL. Autologous T cells expressing anti-CD19 chimeric antigen receptor are now under evaluation in phase 2 studies.

Pathophysiology

The molecular and cellular biology of the disease are complex.

The most frequent genetic alterations in DLCBL are BCL6, BCL2, MYC, and proto-oncogene c-Rel (REL). BCL2 is an anti-apoptotic protein. Expression is detected in 40 to 70% of cases and is associated with an inferior survival. BCL6 is detected in 30 to 40% of patients, and deregulation of BCL6 may block terminal differentiation and provide resistance to apoptotic signals. MYC abnormalities are present in 6 to 9% of cases.

The transcription factor p53 normally induces cell cycle arrest or apoptosis. p53 mutations result in dysregulation of the cell cycle, genomic instability, and proliferation of damaged cells. Mutations in tumor protein p53 (TP53) DNA-binding domains are associated with poor survival in DLBCL. However, there are multiple influences on the p53 pathway, resulting in deregulating p53 and the cell cycle, which are under further study.

What other clinical manifestations may help me to diagnose diffuse large B cell lymphoma?

The clinical manifestations of DLBCL are legion. The classical presentation is lymphadenopathy. Patients may present with "B" symptoms, fevers, night sweats, and weight loss.

Some patients may initially present with normochromic, normocytic, or hypochromic microcytic anemia and an elevated erythrocyte sedimentation rate or C-reactive protein of undetermined etiology.

Extranodal DLBCL was previously defined by the organ involved. Such classifications are not utilized at this time. DLBCL can virtually involve any organ, with the exception of the cornea. Classical extranodal presentations include bone (bone pain or mass), thyroid (enlarging thyroid), pulmonary (mass, dyspnea, or cough), breast, or ocular (orbital mass, visual disturbances).

CNS DLBCL may present in many different ways and are subacute (less than 8 weeks) or insidious (greater than 8 weeks) in onset. Primary DLBCL of the CNS patients may present with memory deficits, visual disturbances, or dementia. Intramedullary cord lesion presentations include back pain, lower motor neuron involvement (areflexia or flaccid paralysis), facial numbness, diplopia, and myelopathy. Primary CNS lymphoma is managed with high-dose methotrexate and rituximab regimens, which may include temozolomide or cytosine arabinoside.

Primary cutaneous DLBCL leg type presents as a lesion on the leg in 85% of patients as a purplish violaceous elevated mass, which may or may not be necrotic.

Patients with DLBCL associated with chronic inflammation and other iatrogenic immunodeficiency-associated lymphoproliferative disorders present like de novo patients with DLBCL.

Patients with stage IE breast and testicular DLBCL are at risk to develop CNS disease. CNS prophylaxis should be utilized in testicular DLBCL, which includes high-dose methotrexate. CNS prophylaxis with six cycles of intrathecal methotrexate for sinus, bone marrow involvement with DLBCL, epidural, and double hit DLBCL is controversial but should be considered. No prospective clinical trials have evaluated CNS prophylaxis.

What other additional laboratory studies may be ordered?

One study reported that circulating 25-hydroxyvitamin D (25[OH]D) levels of less that 25ng/mL were associated with an inferior event free survival and overall survival. Further studies are required to assess whether normalizing vitamin D levels will improve outcomes in these patients. The present recommendation is to replace vitamin D where levels are insufficient.

What’s the evidence?

(This is a recent update of the NCCN clinical practice guidelines which was composed by 30 panel members. Regular updates can be found at www.nccn.org.These guidelines list specific evidence based category numbers. InDLBCL, most are 1 and 2A.)

(This retrospective study reported that an ALC/AMC ratio of greater than or equal to 1.5 was associated with an improved PFS and OS and was independent of the cell of origin immunohistochemistry Hans model.)

(This study confirmed the improvement in outcomes with the addition of rituximab to CHOP chemotherapy, and also reported that there was no role for maintenance rituximab following R-CHOP immunochemotherapy.)

(This study evaluated 60 patients with limited stage disease as defined by the stage-modified IPI and at least one risk factor (nonbulky stage II disease, age greater than 60 years, WHO performance status of two, or elevated serum lactate dehydrogenase). Four doses of rituximab were infused on days -7, 1, 22, and 43, and CHOP was administered on days 3, 24, and 45, followed 3 weeks later by 40 to 46Gy of involved field radiation therapy. At 4 years, the PFS was 88% and the OS was 92%.)

(This is the largest randomized salvage regimen in the management of DLBCL. The outcomes of R-DHAP and R-ICE were the same. The ORR was 63% with a CR rate of 38%. 52% of patients went on to transplant. Patients who relapsed less than 12 months following initial immunochemotherapy had an overall worse outcome with transplant.)

(This was the largest whole-exome sequencing effort in primary DLBCL with 55 primary tumor fresh frozen tissue samples matched with normal tissue. This study demonstrates the biologic heterogeneity of DLBCL. Future studies from this paper will lead to new approaches.)

(Patients at 24 months from the time of diagnosis who were free of disease, had no retreatment, and were alive had an overall survival equivalent to that of the age- and sex-matched general population and this was confirmed in a data set from the Groupe d'Etuda des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien 2003 (LNH2003) program and a registry based in Lyon, France.)

(The overall risk of transformation at 5 years was 2%, highest in patients who were initially observed, and lowest in patients who initially received rituximab monotherapy (14.4% versus 3.2%). The median OS following transformation was 50 months and outcomes were better in patients who transformed after 18 months (5-year OS 66% versus 22%; P < .001).)

(Lymphoma is the fourth most common malignancy that occurs during pregnancy. This was a series from 11 academic health centers. Fifty-six percent (28/50) were DLBCL. Treatments, outcomes and complications were reported.)

(Outcomes of this phase II trial of 64 patients treated with R2CHOP were compared with a retrospective control group. In the RCHOP the 24 month PFS and OS were significantly different (0.28 versus 0.64, p<0.001) and 46% versus 78% (p<0.001) in non-GCB versus GCB patients. In the R2CHOP patients, there was no difference (0.60 versus 0.59) and 83% versus 75% (p=0.61) at two years.)

(In this retrospective series of 680 patients from the Mayo Epidemiology Resource (MER), 64% of relapses were identified prior to a scheduled visit due to patient symptoms. Surveillance scans detected DLBCL relapse prior to clinical manifestations in 9 out of 552 patients (1.6%) observed post-therapy. Four of the eight patients detected via surveillance scans had an equivocal PET scan at the end of treatment. The results were confirmed from a series of 222 patients from Lyon, France with a detection rate of 4 out of 222 patients (1.8%). Eighty-eight percent of the patients in the MER and 91% of patients in the Lyon cohort had symptoms, an abnormal physical examination, and/or elevated LDH levels documented in the medical record.)